Diabetic Autonomic Neuropathy (DAN) is characterized by impairment of autonomic responsiveness of the heart. DAN has been associated with an increased incidence of arrhythmia and sudden death in diabetics. Although the overall incidence of sudden death is lower in women than in men, the risk of sudden death associated with diabetes in women is greater than in men. Studies in postmenopausal women demonstrated that combined estrogen/progestin therapy reduced the incidence of diabetes. Comparison of heart rate variability showed that the parasympathetic response of the heart was increased in young women compared with men;this difference was attenuated after menopause, but maintained in women on hormone replacement therapy (HRT). These data suggested the hypothesis that menopausal women might be more likely to develop DAN and that HRT might protect the heart from development of DAN and decrease the incidence of arrhythmia and sudden death. The Akita mouse manifests a gender difference in the development of diabetes: males develop severe hyperglycemia and secondary effects of diabetes, while females exhibit only a mild hyperglycemia. Using male Akita mice, we have previously developed an animal model for DAN that is characterized by the appearance of spontaneous ventricular arrhythmias following myocardial infarction (MI). Here we propose to test the hypothesis that the female Akita mouse might serve as an animal model for the study of Gender Specific Complications of DAN. Specifically, we will test the hypotheses 1) that ovariectomy of female Akita mice results in the development of the diabetic phenotype and secondary effects of diabetes as demonstrated by the development of hyperglycemia, proteinuria and a decreased parasympathetic inhibition of Isoproterenol-stimulated L-type Ca2+ currents, and that estrogen reverses this effect 2) that estrogen replacement protects ovariectomized female Akita mice against the development of spontaneous ventricular arrhythmias following MI and 3) that gene array studies will establish a subset of genes that are differentially expressed in ovariectomized mice who develop arrhythmias following MI, which might serve as candidate genes for the treatment and prevention of this effect of diabetes in women. Studies in this application propose to establish a unique animal model, which might offer a new gender specific therapeutic approach to diabetes and the complications of DAN. PUBLIC HEALTH RELEVANCE: Diabetic Autonomic Neuropathy (DAN) is characterized by impairment of autonomic responsiveness of the heart and an increased incidence of arrhythmia and sudden death. Data suggest the hypothesis that menopausal women might be more likely to develop DAN and that hormone replacement therapy might protect the heart from development of DAN and decrease the incidence of arrhythmia and sudden death. Here we propose to test the hypothesis that the female Akita mouse might serve as an animal model for the study of Gender Specific Complications of DAN and the protective effects of estrogens against the development of diabetes and its secondary complications in the heart.